The objective of this application is to determine whether let-7 miRNA can be used as a therapy to enhance radiosensitivity in lung cancer treatment. Specific Aim 1: To test the hypothesis that over-expression of let-7 can alter the radiation response in Radelegans and cell lines. a. We will test the effect of let-7 manipulation in Radelegans, a model of reproductive cell death, the primary form of cell death in solid tumors. We will further use Radelegans to understand the genetic basis of the let-7 effects. b. We will evaluate the effect of let-7 manipulation in lung cancer cell lines in standard clonogenic radiosensitivity assays. Specific Aim 2: To test the hypothesis that let-7 over-expression can radiosensitize established invasive KRAS-mediated lung tumors in vivo in an inducible K-Ras mutant mouse model. a. We will test the effect of let-7 over-expression on early K-Ras mediated mouse lung tumors. b. We will test the effect of let-7 over-expression on advanced K-Ras mediated mouse lung tumors. Mice will be intranasally infected with the Ad-cre virus to activate the K-Ras gene to allow tumor progression. After 14 weeks, we will infect the mice with the Ad-let-7 virus, and subject one lung to irradiation and observe for radiosensitization effect. Lung cancer is the major cause of cancer deaths in the US, and existing therapies, including radiotherapy, fail to treat this disease successfully in the overwhelming majority of cases. This work Proposes to use the let-7 microRNA as a therapy to radiosensitize lung cancer.